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'P16INK4a'

Background
P16INK4a is an oncoprotein or known tumor suppressor when over-expressed within the cell-progression pathway of the retinoblastoma protein (pRB). It is a cyclin-dependent kinase inhibitor that will negatively affect proliferation of a natural cell cycle. . The effectiveness of the over-expression occurs between the G1 and S phases of the cell cycle, making it significantly important in the stability of proliferation vs. growth arrest of the cell during the cell cycle. P16INK4's ability to inhibit phosphorylation of the cdk4/6 shifts the balance of pRB not binding to E2F (inactivity) to the binging of pRB to E2F, also known as functional. . The release of E2F from pRB ceases the blocking mechanism of transcription of P16INK4a, leading to the over-expression of functional p16INK4a. Reasoning provides an over-expression of p16INK4a is associated with the presence of Human Papillomavirus.

Role In Cervical Cancer
P16INK4a has been positively correlated to high-risk Human Papillomavirus(HR-HPV)because it inhibits the phosphorylating activity associated with the cdk4/6 - cyclin D complex and the counterparts, retinoblastoma protein (pRB) and the transciption factor E2F. Progression of the cell cycle is controlled by the pRB pathway and its ability to bind to the transciption factor E2F to block the transcription of genes that promote cell proliferation. The pRB pathway is critical for the maintenance of balance between cell cycle continuous and cell cycle rest. . An analysis done by Tsoumpou et al. found that over-expression of P16INK4a increased among cervical smears as cell abnormality increased. . Therefore, the presence of this oncoprotein has major prevalence among HPV and Cervical cancer patients. E6 and E7 are two viral oncoproteins whose interaction with regulatory host genes leads to the disruption of the cell cycle; a direct effect of HPV. E7 directly affects the Impairment of the function of pRB by inhibiting the binding of pRB to E2F, causing an increase in levels of E7 and transciption of genes that promote cell proliferation. .

Structure of Protein
The structure of p16INK4a is tertiary with four helix-turn-helix motifs linked by three loops. . Important recognition binding units have been identified on both p16INK4a and cdk4/6, including a region of 58 residues at cdk4's n terminus for the binding of p16INK4. P16INK4a is a polypeptide chain made up of 156 units, with multiple mutant chains having been synthetically derived. .

Future Importance of P16INK4a
P16INK4a has been discovered to be an important biological marker for the presence of high-rish Human Papillomavirus in patients because of its over-expression due to the disruption of the binding mechanism between the transcription factor E2F and pRB. . P16INK4a is an independent factor from the HR-HPV type and therefore can be used to detect the presence of cervical cancer disease when tested for among HR-HPV and non-HPV patients. . Oncogenic activity among all types of HPV patients can be identified with the blocking of pRB by E7 and the over-expression of p16INK4a caused by this inhibition. Testing for the presence of the over-expression of p16INK4a in pre-cancerous and cancerous individuals is easy and efficient and has become increasingly used among doctors alike.